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Potentiation of temozolomide antitumor effect by purine receptor ligands able to restrain the in vitro growth of human glioblastoma stem cells

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Abstract

Glioblastoma multiforme (GBM), the most common and aggressive brain tumor in humans, comprises a population of stem-like cells (GSCs) that are currently investigated as potential target for GBM therapy. Here, we used GSCs isolated from three different GBM surgical specimens to examine the antitumor activity of purines. Cultured GSCs expressed either metabotropic adenosine P1 and ATP P2Y receptors or ionotropic P2X7 receptors. GSC exposure for 48 h to 10–150 μM ATP, P2R ligand, or to ADPβS or MRS2365, P2Y1R agonists, enhanced cell expansion. This effect was counteracted by the PY1R antagonist MRS2500. In contrast, 48-h treatment with higher doses of ATP or UTP, which binds to P2Y2/4R, or 2′(3′)-O-(4-benzoylbenzoyl)-ATP (Bz-ATP), P2X7R agonist, decreased GSC proliferation. Such a reduction was due to apoptotic or necrotic cell death but mostly to growth arrest. Accordingly, cell regrowth and secondary neurosphere formation were observed 2 weeks after the end of treatment. Suramin, nonselective P2R antagonist, MRS1220 or AZ11645373, selective A3R or P2X7R antagonists, respectively, counteracted ATP antiproliferative effects. AZ11645373 also abolished the inhibitory effect of Bz-ATP low doses on GSC growth. These findings provide important clues on the anticancer potential of ligands for A3R, P2Y1R, and P2X7R, which are involved in the GSC growth control. Interestingly, ATP and BzATP potentiated the cytotoxicity of temozolomide (TMZ), currently used for GBM therapy, enabling it to cause a greater and long-lasting inhibitory effect on GSC duplication when readded to cells previously treated with purine nucleotides plus TMZ. These are the first findings identifying purine nucleotides as able to enhance TMZ antitumor efficacy and might have an immediate translational impact.

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Acknowledgments

The authors declare no conflict of interest. Study supported by a grant to R.C. from the Italian Government (PRIN, prot. 2008H42W5X_002) and in part by a grant to StemTeCh Group from CARICHIETI Foundation. We thank Prof. Marco Marchisio and Dr. Laura Pierdomenico (Dept. of Medicine and Aging Sciences, University of Chieti) for their invaluable support for the experiments in which cytofluorimetric analysis was used to determine the cell cycle distribution.

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    1. Department of Medical, Oral and Biotechnology Sciences, University of Chieti-Pescara, via dei Vestini 29, 66100, Chieti, Italy

      Iolanda D’Alimonte, Eleonora Nargi, Mariachiara Zuccarini, Patrizia Di Iorio, Patricia Giuliani, Francesco Caciagli & Renata Ciccarelli

    2. Department of Medicine and Aging Science, University of Chieti-Pescara, via dei Vestini 29, 66100, Chieti, Italy

      Paola Lanuti

    3. Center for Aging Science, “Università G. D’Annunzio” Foundation, via L. Polacchi 11, 66100, Chieti, Italy

      Paola Lanuti, Patrizia Di Iorio & Francesco Caciagli

    4. StemTeCh Group, via L. Polacchi 11, 66100, Chieti, Italy

      Iolanda D’Alimonte, Eleonora Nargi, Paola Lanuti & Renata Ciccarelli

    5. Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161, Rome, Italy

      Lucia Ricci-Vitiani

    6. Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168, Rome, Italy

      Roberto Pallini

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    Correspondence to Renata Ciccarelli.

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    Francesco Caciagli and Renata Ciccarelli contributed equally to this work.

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    D’Alimonte, I., Nargi, E., Zuccarini, M. et al. Potentiation of temozolomide antitumor effect by purine receptor ligands able to restrain the in vitro growth of human glioblastoma stem cells. Purinergic Signalling 11, 331–346 (2015). https://doi.org/10.1007/s11302-015-9454-7

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